BRIAN R. NOGA, PH.D.

Research Associate Professor, Department of Neurological Surgery

Brain and Spinal Mechanisms Controlling Walking

Research Interests

Impairment of walking and increased pain are debilitating consequences of spinal cord injury (SCI). They occur following the disruption of neuronal pathways that control the spinal locomotor and sensory neurons responsible for the processing of nociceptive (painful) inputs. Fortunately, spinal neurons retain a functional complement of postsynaptic neurotransmitter receptors on their cell membranes following injury, even though the pathways that utilize these receptors are disrupted. This leaves open the possibility that a therapeutic improvement in the control of walking and pain is feasible, providing that the appropriate neurotransmitter is made available to modulate the activity of these neurons. This forms the basis of a “transmitter replacement therapy” following SCI.

Our long-term goal is to develop new therapeutic strategies for enhancing spinal function based on the delivery of neurotransmitters, similarly acting drugs or transplantation of cells secreting these substances. Of the many possible neurotransmitter classes that could be used for this purpose, monoamines hold particular promise as a transmitter replacement candidate. Research from several laboratories support the idea that increased levels of spinal monoamines (serotonin and norepinephrine) can both facilitate locomotion and decrease pain following SCI. Therefore, we have concentrated our recent research effort on understanding the role these transmitters play in the production of locomotion and the control of pain. We have developed biosensors for the detection and measurement of these neurotransmitters to determine the patterns and timescales of release within the spinal cord following activation of the neuronal pathways that utilize them. These studies have shown that the release of these transmitters within the spinal cord is widespread during stimulation and dynamically regulated on a timescale of seconds. In contrast, highly localized spinal monoamine release observed in steady state (at rest) conditions (relevant for ongoing descending modulation of spinal noiciception), may be regulated on a timescale of minutes. In all, these studies demonstrate that in order to affect spinal neurons, serotonin and norepinephrine may not have to be released directly at the synapse, the specialized structure between an axon and the nerve cell receiving its message. Instead, they can trigger transmission of messages when released anywhere around the nerve cells providing they can diffuse to target receptors located some distance from the site of its release. This result implies that regeneration and repair strategies may not require restoration of direct (synaptic) connections in order to affect function. Therefore, duplicating such patterns of release will likely be important for the efficacy of transmitter enhancement strategies for improving locomotion and/or pain.

Recently we have begun to examine how easily these transmitters enter and spread throughout the spinal cord following their exogenous application. This work demonstrates a powerful regulation of extracellular transmitter levels by transporters, diffusion and bulk transport which limit the spread of monoamines in the spinal cord. Thus, only a very small percentage of the transmitter enters the spinal cord when applied to the outside of the spinal cord and concentrations attained within the cord decrease rapidly with depth from surface. This work shows that different methods of delivery can yield different and varying levels of spinal serotonin at a given location and time. The results have implication for the design of neurotransmitter replacement therapies targeting the control of pain and walking following SCI.

Presently, we are investigating the spinal release of monoamines during walking and mapping of the location of contacts (and the receptors involved in communication between these neuronal pathways) between monoaminergic fibers and locomotor-activated neurons within the spinal cord. By comparing the anatomical distribution of contacts between monoamine terminals and pattern generating neurons to the spatial and temporal pattern of monoamine release during locomotion, we hope to be able to eventually duplicate monoamine release in crucial areas of the spinal cord of injured persons and thus facilitate locomotor movement.

This research provides new insight into the processes of locomotion and the dynamic interactive nature of descending systems controlling this behavior. In addition, it also elucidates the mechanisms by which different neurotransmitters facilitate or enable walking. The results of these studies will lead to a better understanding of the major pathways and the key cells involved in the initiation and control of walking.

Illustration of the brain and spinal pathways involved in the production of walking. Stimulation of a higher brain center, the mesencephalic locomotor region (MLR), activates descending pathways within the brainstem, which then activate neurons in the flexor (F) and extensor (E) components of the central pattern generator (CPG) on each side of the spinal cord. The F and E components are also influenced by excitatory () and inhibitory (!) connections from the CPG on the opposite side of the spinal cord. The F and E components influence flexor (fMN) and extensor (eMN) motor neurons that activate leg muscles. Adapted from Noga et al. 2003.